Ferroptosis-related genes influence AML risk through immune cell-mediated pathways: a Mendelian randomization study with mediation analysis.

BACKGROUND: Acute myeloid leukemia (AML) is driven by complex interactions among genetic alterations, metabolic reprogramming, and immune microenvironment dysregulation. Ferroptosis, a form of iron-dependent regulated cell death linking iron metabolism with immune regulation, has been implicated in AML; however, its causal interplay with immune cells remains unclear. Therefore, this study employed a Mendelian randomization (MR) approach to systematically investigate this relationship. METHODS: We conducted a two-sample MR study to investigate the causal effects of ferroptosis-related genes and immune cell subsets on AML risk. Ferroptosis-related genes were obtained from the FerrDb database; corresponding expression quantitative trait loci from the GTEx project were used as instrumental variables. Summary-level genome-wide association study (GWAS) data for AML served as the outcome, and immune cell traits were derived from publicly available immunophenotype GWAS datasets. The inverse variance-weighted method was applied as the primary MR approach, followed by sensitivity analyses. Mediation analyses were performed to quantify the role of immune cells in gene-AML associations. RESULTS: Several ferroptosis-related genes, including SLC40A1, SIRT1, BCAT2, RPL8, and CREB5, were significantly associated with AML risk. Multiple myeloid immune cell subsets mediated part of these effects. No significant heterogeneity or horizontal pleiotropy was observed. CONCLUSIONS: This study provides genetic evidence that ferroptosis-related genes influence AML risk, directly and indirectly, through specific immune cell populations, highlighting the ferroptosis-immune axis as a potential target for AML stratification and therapy.